Vasodilator drug mixture and excipient therefor



Aug. 29, 1967 H. READ I 3,333,787

VASODILATOR DRUG MIXTURE AND EXCIPIENT THEREFOR- Filed Feb. 24, 1964 DIAMETER PARTICLE SIZE DISTRIBUTION ANALYSIS IN MICRONS o o o O m (.0 Q" N HOWARD A. READ INVENTOR.

AGENT.

United States Patent Ofilice Patented Aug. 29, 1967 This invention relates to an improved form of vasodilator drug mixture which is useful for the preparation of pharamaceutical tablets. More particularly, it relates to a high concentration of pentaerythritol tetranitrate (PETN) as the active therapeutic agent in combination with pentaerythritol as the principal excipient.

The use of PETN as the active therapeutic agent in vasodilators is well known as well as the use of various excipients for reducing the explosive sensitivity of PETN for subsequent processing into pharmaceutical tablets. Convention'ally, the tablets are formed by compressing a granulation of the active therapeutic agent in combination with certain inert pharmaceutical excipients. The conventional inert pharmaceutical excipients' include such materials as starch, lactose, terra alba, sucrose, dextrose, sorbitol, mannitol, activated clays, any of the well known gums as well as lubricants such as talc, stearic acid, magnesium stearate and in addition, solubilizing agents and the like. These excipients are desirable in preparing a tablet of convenient size and in addition, serve to reduce the concentration of the PETN during preparation of the tablet to minimize any possible hazards which might result through its handling. Generally, under conventional practice, the amount of PETN by weight of the entire mixture has been held to less than 20%. The more PETN, of course, permit considerably more than 20% by weight. This poses additional problems at these high concentrations for minimizing any possible hazards which might result in preparation of the tablets. The high concentrations of the compounder to prepare tablets of required dosage in a smaller size as well as permit the compounder to add other drugs as desired without excessively increasing the tablet size.

Now, in accordance with the present invention, a

vasodilator drug mixture has been developed which, in

addition to containing a high concentration of PETN, also has the PETN in finely divided form. Etfective oral administration of an orgnaic nitrate therapeutic agent generally requires extremely rapid disintegration of a tablet containing the agent and rapid absorption so that the therapeutic ingredient quickly enters into the blood stream. PETN of extremely fine particle size as encompassed by this invention serves to aid both of the aforementioned requirements.

More specifically, in accordance with the present invention, there is provided a vasodilator drug mixture especially adapted for compounding, the mixture consisting essentially of between 20 and about 35% of PETN having a particle size diameter of not more than 50 microns and between about 6-5 and about 80% of pentaerythritol having a particle size diameter of not more than 100 microns, all percentages being by weight of the mixture and all ingredients being in intimate mixture,

wherein said pentaerythritol is essentially the sole desensitizing excipient or said pentaerythritol and activated clay serve as the desensitizing excipient.

The tests given in the following table demonstrate the recent pharmacoped-ia, however, is demanding of desenitizing effect imparted by the excipients of the vasodilator mixtures containing PETN at concentrations present -111VI1t1011 when utilizing finely divided PETN.

TABLE Test No.

1 2 3 4 6 7 8 9 10 11 PETNType Fine Fine Fine Fine Fine Fine Fine Fine Fine Fine Fine Formula:

PETN, percent 25. 0 25. 0 25. 0 25. 0 25. 0 30. 0 32. 0 35. 0 35. 0 35. 0 35. 0 Pentaerythritol,

percent 75. 0 67. 5 67. 5 68. 4 68. 4 63. 0 59. 5 58. 4 58. 4 58. 4 58. 4 Pharmasorb, percent 7. 5 7. 5 6. 6 6. 6 7. 0 8. 5 6. 6 6. 6 6. 6 6. 6 Cop Sensitivity (2"x 8" Ctg.) F-5 gm. F-5 gm. F-20 gm F-20 gm. F-ZO gm. F-5 gm. F-Army F-Army F#6 F#8 Ti -#8 S-10 gm. S-IO gm. S-2 gm. S-2 gm. S#8 S-Army S-Army Lead Block Compression (Sixteenth in):

5 gm. initiator; 0 1 1 1 0 0 O 0 20 14 15 20 gm. initiator... 1 5 2 3 2 1 2 20 17 17 M.p s Detonation Rate 3" x 24" Ctg. Primer (328 gms. Pentolite). 2 Fail 2 Fail 2Fail 2 Fail 2 Fail 2 Fall 2 Fail 2, 680 2, 340 Fail 2, 800 2, 500 Fail Particle Size of Pentaerythritol Percent we1ghtless than- (Diameter in Microns)' NOTE.B6 cap contains approx. 0.25 gm. PETN. #8 cap contains approx. 0.40 gm. PETN. Army cap contains approx. 0.94 gm. PETN. Other caps contain PETN in the amount given.

With reference to the toreging table, curve A of the appended drawing represents a typical particle size distribution analysis for the Fine PETN used in the tests, and curve B represents a typical particle size distribution analysis for pentaerythritol, which gives efiective desensitization in accordance with the invention. Here it will be seen that the PETN has a particle size diameter of not more than 50 microns and preferably, not more than about 40 microns; also, that the pentaerythritol has a particle size diameter of not more than 100 microns and preferably approximately as follows: 100% finer than 100 microns, 95% finer than 70 microns, 90-95% finer than 50 microns, 65-85% finer than 25 microns, 25-50% finer than 10 microns, and 5-15 less than 5 microns.

From the foregoing table, it will be seen that a decrease in the particle size of the pentaerythritol gives an improvement in desensitizing effect. For example, Test 2, where the particle size of the pentaerythritol exceeded 100 microns, failed to shoot with a 5 gm. booster cap while Tests 3, 4 and 5, where the particle size did not exceed 100 microns, failed to shoot Wtih the large 20 gm. booster caps. Similarly, Test 9, where the particle size of the pentaerythritol exceeded 100 microns, shot with a 8 electric blasting cap while Tests 8, 10 and 11, where the particle size did not exceed 100 microns, failed to shoot with #8 electric blasting caps.

It will be apparent from the table that several tests have been used for establishing criterion denoting degrees of safety for subsequent processing into pharmaceutical tablets. In one test, the drug mixture is packed into 2 diameter x 8 long paper shells and tested with various sized caps to determine if it will shoot. In another test, the drug mixture is packed into 3" diameter x 24 long fiber tubes and tested for propagation when primed with a 328 grams Pentolite (50/50 PETN/TNT) primer. In still another test, 2 pounds of the drug mixture is poured into a half-gallon paper container. The container is placed on a shock plate which rests on top of a loose-fitting piston which in turn is positioned on a lead cylinder block. A booster cap containing either 5 or 20 grams of PETN is used to prime the charge. After firing the cap, the lead cylinder block is removed, and its length is measured in sixteenths of an inch to determine how much it has been compressed relative to its original length. The amount of compression is expressed as a number representing the number of sixteenths of an inch so measured. The low numbers are indicative of low sensitivity.

The drug mixtures in accordance with the present invention and as used in the tests are compounded by simply intimately mixing the finely divided PETN and the excipient. Within the purview of the invention, the ex cipient consists essentially of pentaerythritol alone having a particle size of not more than 100 microns or said pentaerythritol with not more than about by weight of particulate highly porous activated clay. Pharmasorb, which is marketed by Minerals and Chemicals Corporation and which was used in the tests, is representative of the latter class of materials and is an additive commonly used in organic nitrate pharmaceutical mixtures. The Pharmasorb used in the tests was regular grade and had an average particle size of about 3.8 microns. However, other particulate highly porous activated clays including the heat treated clays are commonly available and suitable for this purpose when used up to about 15% and preferably not more than about 10% by Weight of the excipient. The particle size of these clays may range from about 0.01 to about 200 microns, with it being preferred not to exceed about 100 microns in keeping with the desensitizing effect as demonstrated by the maximum particle size diameter for the pentaerythritol.

The ingredients for the drug mixture of this invention may be added separately and intimately mixed, or the excipient first prepared and later mixed with the PETN to form the intimate end product mixture. It will be appreciated that additional materials such as the gums, lubricants, solubilizing agents and the like heretofore mentioned may be incorporated with the drug mixture of this invention. These additional materials ordinarily will not exceed about 10% by weight of the drug mixture and may be incorporated as an add to the mixtures herein described and claimed.

It will be seen, therefore, that this invention may be carried out by the use of various modifications and changes without departing from its spirit and scope, with only such limitations placed thereon as are imposed by the appended claims.

What I claim and desire to protect by Letters Patent is:

1. A vasodilator drug mixture especially adapted for compounding, the mixture consisting essentially of (a) between 20 and about of pentaerythritol tetranitrate having a particle size diameter of not more than microns, and

(b) between about and about 80% of pentaerythritol having a particle size diameter of not more than 100 microns.

2. A vasodilator drug mixture especially adapted for compounding, the mixture consisting essentially of (a) between about 25 and about 35 of pentaerythritol tetranitrate having a particle size diameter of not more than about 40 microns,

(b) between about 55 and about of pentaerythritol having a particle size diameter of not more than 100* microns, and

(c) between about 5 and about 10% of particulate highly porous activated clay, all percentages being by Weight of the mixture and all ingredients being in intimate mixture.

3. A vasodilator drug mixture especially adapted for compounding, the mixture consisting essentially of (a) about 25% of pentaerythritol tetranitrate having a particle size diameter of not more than about 40 microns, and

(b) about of pentaerythritol having a particle size diameter of not more than microns.

4. A vasodilator drug mixture especially adapted for compounding, the mixture consisting essentially of (a) about 25 of pentaerythritol tetranitrate having a particle size diameter of not more than about 40 microns,

(b) about 68% of pentaerythritol having a particle size diameter of not more than 100 microns, and

(c) about 7% of particulate highly porous activated clay, all percentages being by weight of the mixture and all ingredients being in intimate mixture.

5. A vasodilator drug mixture especially adapted for compounding, the mixture consisting essentially of (a) about 30% of pentaerythritol tetranitrate having a particle size diameter of not more than about 40 microns,

(b) about 63% of pentaerythritol having a particle size diameter of not more than 100 microns, and

(c) about 7% of particulate highly porous activated clay, all percentages being by weight of the mixture and all ingredients being in intimate mixture.

6. A vasodilator drug mixture especially adapted for compounding, the mixture consisting essentially of (a) about 35% of pentaerythritol tetranitrate having a particle size diameter of not more than about 40 microns,

(b) about 58% of pentaerythritol having a particle size diameter of not more than 100 microns, and

(c) about 7% of particulate highly porous activated clay, all percentages being by weight of the mixture and all ingredients being in intimate mixture.

7. An excipient especially adapted for desensitizing a vasodilator drug mixture containing more than 20% of pentaerythritol tetranitrate, the excipient consisting essentially of 5 6 (a) pentaerythritol having a particle size diameter of OTHER REFERENCES not more than 100 mlcrons and Beriow et a1.: The Pentaerythritols, Reinhold Publ. (b) not more than about 15% of particulate highly Corp, New York, 1958, pages 259., porous activated clay by welght of the exclplent. C & E News, ,vol. 25, page 1147 (1947) 5 References Cited LEWIS GOTI S, Primary Examiner. UNITED STATES PATENTS ALBERT T. MEYERS, Examiner.

3,096,242 7/1963 Young 16765 G. A. MENTIS, S. K. ROSE, Assistant Examiners. 

1. A VASODILATOR DRUG MIXTURE ESPECIALLY ADAPTED FOR COMPOUNDING, THE MIXTURE CONSISTING ESSENTIALLY OF (A) BETWEEN 20 AND ABOUT 35% OF PENTAERYTHRITOL TETRANITRATE HAVING A PARTICLE SIZE DIAMETER OF NOT MORE THAN 50 MICRONS, AND (B) BETWEEN ABOUT 65 AND ABOUT 80% OF PENTAERTHRITOL HAVING A PARTICLE SIZE DIAMETER OF NOT MORE THAN 100 MICRONS. 